Radiosensitisation by pharmacological ascorbate in glioblastoma multiforme cells, human glial cells, and HUVECs depends on their antioxidant and DNA repair capabilities and is not cancer specific

Castro, M. Leticia; McConnell, Melanie J.; Herst, Patries M.

doi:10.1016/j.freeradbiomed.2014.06.022

Cited by 28 publications

(43 citation statements)

References 42 publications

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“…This, in turn, increases the intracellular H 2 O 2 [25] to substantially higher levels than physiological concentrations. Extracellular P-AscH - has also been shown to induce DNA damage (mitochondrial and nuclear) in addition to ATP depletion via H 2 O 2 [1, 2, 13, 15, 22–24, 26–27]. Again, introducing extracellular catalase to the P-AscH - culture prevented ATP depletion which supports the hypothesis that ascorbate-mediated ATP depletion is via the extracellular H 2 O 2 produced that permeates the cell.…”

Section: Introductionsupporting

confidence: 56%

Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy

et al. 2017

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Cancer cell toxicity to therapeutic H2O2 varies widely depending on cell type. Interestingly, it has been observed that different cancer cell types have varying peroxiporin expression. We hypothesize that variation in peroxiporin expression can alter cell susceptibility to therapeutic H2O2 concentrations. Here, we silence peroxiporin aquaporin-3 (AQP3) on the pancreatic cancer cell line MIA PaCa-2 and compare clonogenic survival response to the wild-type. The results showed a significantly higher surviving fraction in the clonogenic response for siAQP3 MIA PaCa-2 cells at therapeutic H2O2 doses (P < 0.05). These results suggest that peroxiporin expression is significant in modulating the susceptibility of cancer cells to ascorbate therapy.

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Section: Introductionsupporting

confidence: 56%

Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy

et al. 2017

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“…It has previously been observed that P-AscH − can result in the loss of intracellular ATP [1], [3], [10], [55], [56]. P-AscH − decreased the intracellular concentration of ATP in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 69%

“…While this selective cytotoxicity has been observed to be dependent on the generation of H 2 O 2 , the mechanism by which this occurs is still under investigation. Several mechanisms for how the H 2 O 2 generated by P-AscH − elicits its cytotoxicity to tumor cells have been hypothesized and examined, for example: DNA damage [3], [13], [52], [55], [56], [57]; and the depletion of ATP leading to tumor cell death [1], [3], [10], [58], [59]. H 2 O 2 plays an integral role in the mechanism.…”

Section: Discussionmentioning

confidence: 99%

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

et al. 2016

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Ascorbate (AscH−) functions as a versatile reducing agent. At pharmacological doses (P-AscH−; [plasma AscH−] ≥≈20 mM), achievable through intravenous delivery, oxidation of P-AscH− can produce a high flux of H2O2 in tumors. Catalase is the major enzyme for detoxifying high concentrations of H2O2. We hypothesize that sensitivity of tumor cells to P-AscH− compared to normal cells is due to their lower capacity to metabolize H2O2. Rate constants for removal of H2O2 (kcell) and catalase activities were determined for 15 tumor and 10 normal cell lines of various tissue types. A differential in the capacity of cells to remove H2O2 was revealed, with the average kcell for normal cells being twice that of tumor cells. The ED50 (50% clonogenic survival) of P-AscH− correlated directly with kcell and catalase activity. Catalase activity could present a promising indicator of which tumors may respond to P-AscH−.

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“…( 1 )]. Hydrogen peroxide diffuses into cells where it generates reactive oxygen species (ROS), such as hydroxyl radicals ( 6 ), which overwhelm the anti-oxidant defense system, resulting in DNA damage ( 7 , 8 ). The extracellular addition of catalase abrogates the pro-oxidant effect of high-dose ascorbate ( 6 – 9 ), verifying the role of extracellular hydrogen peroxide in its mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

“…Two in vitro studies have shown that high-dose ascorbate radiosensitized primary GBM cells isolated from tumors of GBM patients by generating extracellular hydrogen peroxide and inducing S/G2 arrest, interfering with DNA repair ( 7 , 8 ). Interestingly, both ionizing radiation and high-dose ascorbate were shown to increase labile iron levels in pancreatic tumor homogenates from athymic nude mice ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

et al. 2014

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Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8–45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.

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Radiosensitisation by pharmacological ascorbate in glioblastoma multiforme cells, human glial cells, and HUVECs depends on their antioxidant and DNA repair capabilities and is not cancer specific

Cited by 28 publications

References 42 publications

Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy

Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

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